2-bromo-9alpha-fluorohydrocortisone and 21-esters thereof



Unite States Patent '0 Z-BROMO-9a-FLUOROHYDROCORTI ONE ANDZI-ESTERSTHEREOF Josef Fried, New Brunswick, N. .L, assignor to OlinMathieson Chemical Corporation, New York, N. Y., a corporation ofVirginia No Drawing. Application June 28, 1955 Serial No. 518,680

3 Claims. (Cl-1 260397.45)

This application is a continuation-in-part of my patent application,Serial No. 489,769, filed February, 21, 1955, which in turn is acontinuation-in-part of my parent applications, Serial No. 417,489,filed MarchlO, 1954, and Serial No. 343,243, filed March 18, 1953, nowabandoned.

This invention relates to synthesis of valuable steroids.

In my parent application, Serial No. 489,769, I disclose a process forconverting 2,4-dibromo-9a-fluoroallopregnane-l16,17a,21-triol-3,20-dioneand 21-esters thereof (particularly the 21-acetate) to the following:9a-fluoro- A -pregnadiene-I 1B,17a,2lt1'i01-3,20 dione; 9a fluoro- A-pregnadiene-1 1 fl,17a,21-ttiOl-3,20-di011e; and 21-esters (e. g.ZI-acetates) thereof. This conversion is most readily effected byheating the dibromide with an organic base, such as a lower alkylatedpyridine (e. g. collidine), the two resulting steroids then beingseparated from the reaction mixture by chromatography.

I have now discovered that if this conversion is done on a large scale,three additional hitherto undisclosed, physiologically active steroidsare produced. These three newly discovered steroids are:2-bromo-9oc-fluoro-A -preguene-l1(3,17a,-21-triol-3,20-dione and21-esters thereof; 2-bromo-9a fluorohydrocortisone and 21-estersthereof; and an isomer of 9a-fluoro-A -pregnadiene-11B,17a,21-triol-3,20-clione and 2l-esters thereof. Among the utilizableesterifying acids may be mentioned the carboxylic acids, especiallyhydrocarbon carboxylic acids containing less than ten carbon atoms asexemplified by the lower alkanoic acids (e. g. acetic, propionic,butyric and enanthic) aromatic hydrocarbon carboxylic acids (e. g.benzoic acid), and hydrocarbon aralkanoic acids (e. g. phenylacetic andB-phenylpropionic acid). The five steroid products are separated bychromatography, as more fully detailed in the following example.

If a 21-ester is initially formed, it can be hydrolized to the free21-01 by treatment with a base, such as an alkali metal salt of carbonicacid (e. g. potassium carbonate). Furthermore, the llfi-hydroxy steroidscan be oxidized with a hexavalent chromium compound (e. g. chromic acid)in an organic acid (e. g. acetic acid) to the corresponding ll-ketoderivatives.

The following examples are illustrative of the invention (alltemperatures being in centigrade):

EXAMPLE 1 (a) 2-br0m0-9a-flu0r0-A -pregnene-1 1 [3,171 21 -tril-3,20-dione 21 -acetate A solution of 20.7 g. of crude2,4-dibromo-9u-fluoroallopregnane-l1,8,l7a,21-triol-3,20-dione2l-acetate in 150 ml. of collidine is refluxed under nitrogen for 45minutes. Concentration of the reaction mixture in high vacuum results ina syrupy residue, which is taken up in chloroform and extracted withdilute sulfuric acid to remove all residual collidine. The chloroformextract is then washed with dilute sodium bicarbonate and water andevaporated to dryness in vacuo. The residue (about 11.7 g.) is dissolvedin 100 ml. of chloroform and 300 m1.

2,848,464 ,BatentedAug. L9, 1958 ice of benzene ,and chromatographed on150 g..of sulfuric acid-washed alumina. Elution of the column with 1part chloroform and 3 .parts benzene (5,000 ml.) affords2-bromo-9ot-flu0ro-A pregnene 11B,17u,21 triol 3,20-

-.dione,21acetate (about 1.1. g. crude) which after recrystallizationfrom alcohol has the following properties: M. P. about 184-185-'aftermelting and resolidification at about 126-139"; [M +79 (c. 0.99 in('acetylated side chain), 5.90 6.98 6.24, (2-bromo- A '-3-ketone) (b)2-bromo-9wfluorohydracortisone '21-acetate (2-br0-mo-Qa-fluoro-M-pregnene-I1B,17a,21-tri0l 3,20 dione 21 -acetate) Furtherelution of the column with 1 part chloroform and 2 parts benzene (2000ml.) furnishes 2-bromo-9afluoro-A -pregnene-l1,8,17a,21-triol-3,20-dione21-acetate (about 750 mg. crude), which after crystallization from 95%alcohol has the following properties: M. P. about 174-175; [a] +l36 (c.0.80 in CHCl A3,}; 242 m (e=12,200); REES, 2.85-295 (OH), 5.78 1, 5.85;;(acetylated side chain), 594 6.15;; (2-bromo- A -3-ketone)Analysis.-Calcd. for C H o FBr: C, 55.09; H, 6.17; Br. 15.96. Found: C,55.70; H, 6.30; Br, 15.16.

2-brorno-9u-fluorohydrocortisone 21-acetate is about as active ashydrocortisone in the rat liver glycogen assay and hence is aglucocorticoid which can be used instead of hydrocortisone or cortisonein the treatment of rheumatoid arthritis or dermatomyositis. It isfurther useful as an intermediate in the preparation of 9u-fluoro-A-pregnadiene-l1,8,17a,21-triol-3,20-dione 21-acetate and 9ailuOrO-M-pregnadiene-Il 8,l7a,2l-triol 3,20 dione 21- acetate by renewedtreatment with boiling collidine.

(c) 6-dehydro-9wfluomhydrocortisone 21-acetate and 1-dehydr0-9rx-flurorohydrocortisone 21 -acetate (9a-flu0r0 A-pregnadiene-1l {3,1 7ot,21 -triol-3,20-di0ne 21 acetate and 9u-flu0ra-A-pregnadiene-11,9,17a,21-tri0l 3,20- dione 21-acetate) Continuedelutionwith chloroform containing 5% acetone (10,000 ml.) elutes6-dehydro-9'a-fiuorohydrocortisone acetate (about 2.1 g. crude), whichafter recrystallization from acetone-hexane has the followingproperties: M. P. about 216217; [a] +123 (c. 0.36 in 95% alcohol), (c.0.36 in CHCl 7022,, 281 m (e=23,000) [see Serial No. 489,769]

6-dehydro-9a-fiuorohydrocortisone acetate is followed on the column[same eluant as above (5,000 ml.) and chloroform containing 7.5% acetone(12,000 ml.)] by 1- dehydro-9a-fluorohydrocortisone acetate (about 700mg. crude), which after recrystallization from acetone-hexane (2crystalline forms, needles which spontaneously change into prisms) hasthe following properties: M. P. about 243245, [mi +990 (c. 0.78 inacetone);

N512, 238 m (15,000) [see serial No. 489,769]

(d) Isomer of 1 dehydro-9u fluorohydrocortisone 21- acetate Finalelution of the column with 10% acetone in chloroform (7,000 ml.)followed by 15% acetone in chloroform (4,500 ml.) produces an isomer ofl-dehydro-9afiuorohydrocortisone acetate, which after crystallizationfrom alcohol has the following properties: M. P. about 271-272", [111+73 (c. 0.59 in alcohol),

EXAMPLE 2 A solution of 730 mg. of 2,4-dibromo-9a-fluoroallopregnane-l1p,l7a,21-trio1-3,20-dione 21-acetate in2 ml. of collidine is heated at 100 under nitrogen for 2 hours. Thereaction mixture is dissolved in chloroform and extracted with dilutesulfuric acid, water, dilute bicarbonate and again with water. Thechloroform solution is evaporated to dryness in vacuo and the residue(about 490 4 mg.) chromatographed on 10 g. of acid washed alumina. Amixture of benzene and chloroform (3:1, 900 ml.) elutes about 197 mg. ofcrude 2-bromo-9a-fluorohydrocortisone acetate, which afterrecrystallization from acetone hexane has M. P. about 163l64 and [011142 (c. 0.73 in CHCI Its infra-red spectrum in chloroform is identicalwith that of the product described in Example 1, step b.

The invention may be otherwise variously embodied within the scope ofthe appended claims.

1 claim: 7

1. A steroid selected from the group consisting of 2-bromo-9a-fluorohydrocortisone and 21-esters thereof with hydrocarboncarboxylic acids of less than ten carbon atoms.

2. A 2l-ester of 2-bromo-9a-fluorohydrocortisone with a hydrocarboncarboxylic acid of less than ten carbon atoms.

3. The ester of claim 2 wherein the carboxylic acid is acetic acid.

References Cited in the file of this patent UNITED STATES PATENTS2,783,226 Gould et al Feb. 26, 1957 UNITED STATES PATENT OFFICECertificate of Correction Patent No. 2,848,464 August 19, 1958 JosefFried It is hereby certified that error appears in the printedspecification of the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 2, line 5, for 21acetate read 21-acetate; line 31, for 2-85-2951.read 2.852.95,u; line 67, for +990 read 99-.

Signed and sealed this 11th day of November 1958.

[SEAL] Attest: KARL H. AXLINE, ROBERT C. WATSON,

Attesting Oyfioer. Uommz'sm'oner of Patents.

1. A STEROID SELECTED FROM THE GROUP CONSISTING OF2BROMO-9A-FLUOROHYDROCORTISONE AND 21-ESTERS THEREOF WITH HYDROCARBONCARBOXYLIC ACIDS OF LESS THAN TEN CARBON ATOMS.